Harper's Biochemistry Chapter 11 - Bioenergetics.PDF

S E C T I O N Bioenergetics III C H A P T E R Bioenergetics: The Role of ATP Kathleen M. Botham, PhD, DSc, & Peter A. Maye...

S E C T I O N Bioenergetics III C H A P T E R Bioenergetics: The Role of ATP Kathleen M. Botham, PhD, DSc, & Peter A. Mayes, PhD, DSc 11 OBJ E C TI VE S State the first and second laws of thermodynamics and understand how they apply to biologic systems. After studying this chapter, Explain what is meant by the terms free energy, entropy, enthalpy, exergonic, you should be able to: and endergonic. Appreciate how reactions that are endergonic may be driven by coupling to those that are exergonic in biologic systems. Explain the role of group transfer potential, adenosine triphosphate (ATP), and other nucleotide triphosphates in the transfer of free energy from exergonic to endergonic processes, enabling them to act as the “energy currency” of cells. BIOMEDICAL IMPORTANCE FREE ENERGY IS THE USEFUL Bioenergetics, or biochemical thermodynamics, is the study ENERGY IN A SYSTEM of the energy changes accompanying biochemical reactions. Gibbs change in free energy (ΔG) is that portion of the Biologic systems are essentially isothermic and use chemical total energy change in a system that is available for doing energy to power living processes. The way in which an ani- work—that is, the useful energy, also known as the chemical mal obtains suitable fuel from its food to provide this energy potential. is basic to the understanding of normal nutrition and metab- olism. Death from starvation occurs when available energy reserves are depleted, and certain forms of malnutrition are Biologic Systems Conform to the associated with energy imbalance (marasmus). Thyroid hor- General Laws of Thermodynamics mones control the metabolic rate (rate of energy release), and The first law of thermodynamics states that the total energy disease results if they malfunction. Excess storage of surplus of a system, including its surroundings, remains constant. energy causes obesity, an increasingly common disease of It implies that within the total system, energy is neither lost Western society which predisposes to many diseases, includ- nor gained during any change. However, energy may be ing cardiovascular disease and diabetes mellitus type 2, and transferred from one part of the system to another, or may be lowers life expectancy. transformed into another form of energy. In living systems, 109 110 SECTION III Bioenergetics chemical energy may be transformed into heat or into electri- A cal, radiant, or mechanical energy. The second law of thermodynamics states that the total Heat Ex entropy of a system must increase if a process is to occur er go D spontaneously. Entropy is the extent of disorder or random- nic ness of the system and becomes maximum as equilibrium is Free energy approached. Under conditions of constant temperature and pressure, the relationship between the free-energy change (ΔG) of a reacting system and the change in entropy (ΔS) is Chemical expressed by the following equation, which combines the two nic energy go laws of thermodynamics: d er En ∆G = ∆H −T∆S where ΔH is the change in enthalpy (heat) and T is the abso- C B lute temperature. A+C B + D + Heat In biochemical reactions, since ΔH is approximately equal to the total change in internal energy of the reaction or ΔE, FIGURE 11–1 Coupling of an exergonic to an endergonic the above relationship may be expressed in the following way: reaction. ∆G = ∆E −T∆S If ΔG is negative, the reaction proceeds spontaneously with may be represented as shown in Figure 11–1. The conversion loss of free energy, that is, it is exergonic. If, in addition, ΔG is of metabolite A to metabolite B occurs with release of free of great magnitude, the reaction goes virtually to completion energy and is coupled to another reaction in which free energy and is essentially irreversible. On the other hand, if ΔG is posi- is required to convert metabolite C to metabolite D. The terms tive, the reaction proceeds only if free energy can be gained, exergonic and endergonic, rather than the normal chemical that is, it is endergonic. If, in addition, the magnitude of ΔG is terms “exothermic” and “endothermic,” are used to indicate great, the system is stable, with little or no tendency for a reac- that a process is accompanied by loss or gain, respectively, of tion to occur. If ΔG is zero, the system is at equilibrium and no free energy in any form, not necessarily as heat. In practice, an net change takes place. endergonic process cannot exist independently, but must be a When the reactants are present in concentrations of component of a coupled exergonic–endergonic system where 1.0 mol/L, ΔG0 is the standard free-energy change. For bio- the overall net change is exergonic. The exergonic reactions chemical reactions, a standard state is defined as having a pH are termed catabolism (generally, the breakdown or oxidation of 7.0. The standard free-energy change at this standard state of fuel molecules), whereas the synthetic reactions that build is denoted by ΔG0′. up substances are termed anabolism. The combined catabolic The standard free-energy change can be calculated from and anabolic processes constitute metabolism. the equilibrium constant Keq, If the reaction shown in Figure 11–1 is to go from left to right, then the overall process must be accompanied by loss ∆G 0′ = −RT ln Keq of free energy as heat. One possible mechanism of coupling could be envisaged if a common obligatory intermediate (I) where R is the gas constant and T is the absolute temperature took part in both reactions, that is, (see Chapter 8). It is important to note that the actual ΔG may be larger or smaller than ΔG0′ depending on the concentra- A+C→I→B+D tions of the various reactants, including the solvent, various ions, and proteins. Some exergonic and endergonic reactions in biologic systems In a biochemical system, an enzyme only speeds up the are coupled in this way. This type of system has a built-in mech- attainment of equilibrium; it never alters the final concentra- anism for biologic control of the rate of oxidative processes tions of the reactants at equilibrium. since the common obligatory intermediate allows the rate of utilization of the product of the synthetic path (D) to deter- mine by mass action the rate at which A is oxidized. Indeed, ENDERGONIC PROCESSES these relationships supply a basis for the concept of respiratory PROCEED BY COUPLING TO control, the process that prevents an organism from burning out of control. An extension of the coupling concept is pro- EXERGONIC PROCESSES vided by dehydrogenation reactions, which are coupled to The vital processes—for example, biosynthetic reactions, hydrogenations by an intermediate carrier (Figure 11–2). muscular contraction, nerve impulse conduction, and active An alternative method of coupling an exergonic to an end- transport—obtain energy by chemical linkage, or coupling, to ergonic process is to synthesize a compound of high-energy oxidative reactions. In its simplest form, this type of coupling potential in the exergonic reaction and to incorporate this  CHAPTER 11 Bioenergetics: The Role of ATP 111 AH2 Carrier BH2 The Intermediate Value for the Free Energy of Hydrolysis of ATP Has A Carrier H2 B Important Bioenergetic Significance FIGURE 11–2 Coupling of dehydrogenation and hydrogena- The standard free energy of hydrolysis of a number of bio- tion reactions by an intermediate carrier. chemically important phosphates is shown in Table 11–1. An estimate of the comparative tendency of each of the phosphate new compound into the endergonic reaction, thus effecting groups to transfer to a suitable acceptor may be obtained from a transference of free energy from the exergonic to the ender- the ΔG0′ of hydrolysis at 37°C. This is termed the group trans- gonic pathway. The biologic advantage of this mechanism is fer potential. The value for the hydrolysis of the terminal phos- that the compound of high potential energy, ~ , unlike I in phate of ATP (when ATP is converted to ADP + Pi) divides the previous system, need not be structurally related to A, B, the list into two groups. Low-energy phosphates, having a low C, or D, allowing to serve as a transducer of energy from a group transfer potential, exemplified by the ester phosphates wide range of exergonic reactions to an equally wide range of found in the intermediates of glycolysis, have G0′ values smaller endergonic reactions or processes, such as biosynthesis, mus- than that of ATP, while in high-energy phosphates, with a cular contraction, nervous excitation, and active transport. In more negative G0′, the value is higher than that of ATP. The the living cell, the principal high-energy intermediate or car- components of this latter group, including ATP, are usually rier compound is ATP (Figure 11–3). anhydrides (eg, the 1-phosphate of 1,3-bisphosphoglycerate), enol phosphates (eg, phosphoenolpyruvate), and phosphogua- nidines (eg, creatine phosphate, arginine phosphate). HIGH-ENERGY PHOSPHATES The symbol ~ P indicates that the group attached to the PLAY A CENTRAL ROLE IN ENERGY bond, on transfer to an appropriate acceptor, results in trans- fer of the larger quantity of free energy. Thus, ATP has a high CAPTURE & TRANSFER group transfer potential, whereas the phosphate in adenosine In order to maintain living processes, all organisms must obtain monophosphate (AMP) is of the low-energy type since it is a supplies of free energy from their environment. Autotrophic normal ester link (Figure 11–4). In energy transfer reactions, organisms utilize simple exergonic processes; for example, the ATP may be converted to ADP and Pi or, in reactions requir- energy of sunlight (green plants), the reaction Fe2+ → Fe3+ ing a greater energy input, to AMP + PPi (see Table 11–1). (some bacteria). On the other hand, heterotrophic organ- isms obtain free energy by coupling their metabolism to the TABLE 11–1 Standard Free Energy of Hydrolysis of breakdown of complex organic molecules in their environ- Some Organophosphates of Biochemical Importance ment. In all these organisms, ATP plays a central role in the transference of free energy from the exergonic to the ender- DG0 gonic processes. ATP is a nucleotide consisting of the nucleo- Compound kJ/mol kcal/mol side adenosine (adenine linked to ribose) and three phosphate groups (see Chapter 32). In its reactions in the cell, it functions Phosphoenolpyruvate −61.9 −14.8 as the Mg2+ complex (see Figure 11–3). Carbamoyl phosphate −51.4 −12.3 The importance of phosphates in intermediary metabo- 1,3-Bisphosphoglycerate −49.3 −11.8 lism became evident with the discovery of the role of ATP, (to 3-phosphoglycerate) adenosine diphosphate (ADP), and inorganic phosphate (Pi) Creatine phosphate −43.1 −10.3 in glycolysis (see Chapter 17). ATP → AMP + PPi −32.2 −7.7 NH2 ATP → ADP + Pi −30.5 −7.3 N N Glucose-1-phosphate −20.9 −5.0 Mg2+ N PPi −19.2 −4.6 N Fructose-6-phosphate −15.9 −3.8 O– O– O– –O P O P O P O CH2 O Glucose-6-phosphate −13.8 −3.3 O O O C C Glycerol-3-phosphate −9.2 −2.2 H H Abbreviations: PPi, pyrophosphate; Pi, inorganic orthophosphate. ATP H H Note: All values are taken from Jencks WP: Free energies of hydrolysis and decarboxylation. In: Handbook of Biochemistry and Molecular Biology, vol 1. Physical and Chemical Data. OH OH Fasman GD (editor). CRC Press, 1976:296-304, except that for PPi which is from Frey PA, Arabshahi A: Standard free-energy change for the hydrolysis of the alpha, beta- phosphoanhydride bridge in ATP. Biochemistry 1995;34:11307. Values differ between FIGURE 11–3 Adenosine triphosphate (ATP) is shown as the investigators, depending on the precise conditions under which the measurements magnesium complex. were made. 112 SECTION III Bioenergetics O– O– O– products of hydrolysis, ADP and orthophosphate, are more stable, and so lower in energy, than ATP (Figure 11–5). Other Adenosine O P O P O P O– “high-energy compounds” are thiol esters involving coenzyme O O O A (eg, acetyl-CoA), acyl carrier protein, amino acid esters involved in protein synthesis, S-adenosylmethionine (active or Adenosine P P P methionine), uridine diphosphate glucose (UDPGlc), and Adenosine triphosphate (ATP) 5-phosphoribosyl-1-pyrophosphate (PRPP). Adenosine P P Adenosine P Adenosine diphosphate (ADP) Adenosine monophosphate (AMP) ATP ACTS AS THE “ENERGY CURRENCY” OF THE CELL FIGURE 11–4 Structure of ATP, ADP, and AMP showing the The high group transfer potential of ATP enables it to act as position and the number of high-energy phosphates (~ ). a donor of high-energy phosphate to form those compounds below it in Table 11–1. Likewise, with the necessary enzymes, The intermediate position of ATP allows it to play an ADP can accept phosphate groups to form ATP from those important role in energy transfer. The high free-energy change compounds above ATP in the table. In effect, an ATP/ADP on hydrolysis of ATP is not in itself caused by the breaking cycle connects those processes that generate ~ to those pro- of the P-O bond linking the terminal phosphate to the mol- cesses that utilize ~ (Figure 11–6), continuously consuming ecule (see Figure 11–4), in fact, energy is needed to bring and regenerating ATP. This occurs at a very rapid rate since this about. It is the consequences of this bond breakage that the total ATP/ADP pool is extremely small and sufficient to cause net energy to be released. Firstly, there is strong electro- maintain an active tissue for only a few seconds. static repulsion between the negatively charged oxygen atoms There are three major sources of ~ taking part in energy in the adjacent phosphate groups of ATP (see Figure 11–4), conservation or energy capture: which destabilizes the molecule and makes the removal of one phosphate group energetically favorable. Secondly, the ortho- 1. Oxidative phosphorylation is the greatest quantitative phosphate produced is greatly stabilized by the formation of source of ~ in aerobic organisms. ATP is generated in the resonance hybrids in which the three negative charges are mitochondrial matrix as O2 is reduced to H2O by electrons shared between the four oxygen atoms. Overall, therefore, the passing down the respiratory chain (see Chapter 13). FIGURE 11–5 The free-energy change on hydrolysis of ATP to ADP. Initially, energy input is required to break the terminal P-O bond. However, the breaking of the bond relieves the strong electrostatic repulsion between the negatively charged oxygen atoms in the adjacent phosphate groups of ATP, making the removal of one phosphate group energetically favorable. In addition, the orthophosphate released is greatly stabilized by the formation of resonance hybrids in which the three negative charges are shared between the four oxygen atoms. These effects more than compensate for the initial energy input and result in the high free-energy change seen when ATP is hydrolyzed to ADP.  CHAPTER 11 Bioenergetics: The Role of ATP 113 Phosphoenolpyruvate 1,3-Bisphosphoglycerate ATP Allows the Coupling of Succinyl- CoA Oxidative phosphorylation Thermodynamically Unfavorable Creatine P Reactions to Favorable Ones P Endergonic reactions cannot proceed without an input of free (Store of P ) energy. For example, the phosphorylation of glucose to glucose- ATP Creatine 6-phosphate, the first reaction of glycolysis (see Figure 17–2): Glucose + Pi → Glucose-6-phosphate + H2O ATP/ADP cycle (DG0) = +13.8 kJ/mol (1) P Glucose-6-phosphate ADP Other phosphorylations, is highly endergonic and cannot proceed under physiologic activations, conditions. Thus, in order to take place, the reaction must be Glucose-1,6- and endergonic Glycerol-3-phosphate bisphosphate processes coupled with another—more exergonic—reaction such as the hydrolysis of the terminal phosphate of ATP. FIGURE 11–6 Role of ATP/ADP cycle in transfer of high- energy phosphate. ATP → ADP + Pi (ΔG0′ = −30.5 kJ/mol) (2) When (1) and (2) are coupled in a reaction catalyzed by 2. Glycolysis. A net formation of two ~ results from the for- hexokinase, phosphorylation of glucose readily proceeds in a mation of lactate from one molecule of glucose, generated highly exergonic reaction that under physiologic conditions in two reactions catalyzed by phosphoglycerate kinase and is irreversible. Many “activation” reactions follow this pattern. pyruvate kinase, respectively (see Chapter 17). 3. The citric acid cycle. One ~ is generated directly in the Adenylyl Kinase (Myokinase) cycle at the succinate thiokinase step (see Figure 16–3). Interconverts Adenine Nucleotides Phosphagens act as storage forms of group transfer poten- This enzyme is present in most cells. It catalyzes the following tial and include creatine phosphate, which occurs in vertebrate reaction: skeletal muscle, heart, spermatozoa, and brain, and arginine phosphate, which occurs in invertebrate muscle. When ATP is rapidly being utilized as a source of energy for muscular contrac- tion, phosphagens permit its concentrations to be maintained, but when the ATP/ADP ratio is high, their concentration can increase to act as an energy store (Figure 11–7). Adenylyl kinase is important for the maintenance of energy When ATP acts as a phosphate donor to form com- homeostasis in cells because it allows: pounds of lower free energy of hydrolysis (see Table 11–1), 1. The group transfer potential in ADP to be used in the syn- the phosphate group is invariably converted to one of low thesis of ATP. energy. For example, the phosphorylation of glycerol to form glycerol-3-phosphate: 2. The AMP formed as a consequence of activating reactions involving ATP to be rephosphorylated to ADP. GLYCEROL KINASE 3. AMP to increase in concentration when ATP becomes Glycerol + Adenosine P P P depleted so that it is able to act as a metabolic (allosteric) signal to increase the rate of catabolic reactions, which in Glycerol P + Adenosine P P turn lead to the generation of more ATP (see Chapter 14). When ATP Forms AMP, Inorganic Pyrophosphate (PPi) Is Produced ATP can also be hydrolyzed directly to AMP, with the release of PPi (see Table 11–1). This occurs, for example, in the activa- tion of long-chain fatty acids (see Figure 22–3). This reaction is accompanied by loss of free energy as heat, which ensures that the activation reaction will go to the right, and is further aided by the hydrolytic splitting of PPi, FIGURE 11–7 Transfer of high-energy phosphate between catalyzed by inorganic pyrophosphatase, a reaction that itself ATP and creatine. has a large ΔG0′ of −19.2 kJ/mol. Note that activations via the 114 SECTION III Bioenergetics Inorganic All of these triphosphates take part in phosphorylations in the pyrophosphatase cell. Similarly, specific nucleoside monophosphate (NMP) 2Pi kinases catalyze the formation of NDP from the correspond- ing monophosphates. Thus, adenylyl kinase is a specialized Pi PPi NMP kinase. Acyl-CoA synthetase, etc SUMMARY Biologic systems use chemical energy to power living processes. ATP Exergonic reactions take place spontaneously with loss of free energy (ΔG is negative). Endergonic reactions require the gain of free energy (ΔG is positive) and occur only when coupled to exergonic reactions. X2 ADP AMP ATP acts as the “energy currency” of the cell, transferring free Adenylyl kinase energy derived from substances of higher energy potential to those of lower energy potential. FIGURE 11–8 Phosphate cycles and interchange of adenine nucleotides. REFERENCES Haynie D: Biological Thermodynamics. Cambridge University Press, pyrophosphate pathway result in the loss of two ~ rather 2008. than one, as occurs when ADP and Pi are formed. Nicholls DG, Ferguson S: Bioenergetics, 4th ed. Academic Press, 2013. A combination of the above reactions makes it possible for phosphate to be recycled and the adenine nucleotides to inter- change (Figure 11–8). Other Nucleoside Triphosphates Participate in Group Transfer Potential By means of the nucleoside diphosphate (NDP) kinases, UTP, GTP, and CTP can be synthesized from their diphos- phates, for example, UDP reacts with ATP to form UTP.